Management of Bone Metastases A Multidisciplinary Guide Vincenzo Denaro Alberto Di Martino Andrea Piccioli Editors 123 Management of Bone Metastases Vincenzo Denaro • Alberto Di Martino Andrea Piccioli Editors Management of Bone Metastases A Multidisciplinary Guide Editors Vincenzo Denaro Alberto Di Martino Department of Orthopaedics and Department of Orthopaedics and Trauma Surgery Trauma Surgery University Campus Bio-Medico of Rome University Campus Bio-Medico of Rome Rome Rome Italy Italy Andrea Piccioli General Direction of Health Program National Ministry of Health of Italy Rome Italy ISBN 978-3-319-73484-2 ISBN 978-3-319-73485-9 (eBook) https://doi.org/10.1007/978-3-319-73485-9 Library of Congress Control Number: 2018943688 © Springer International Publishing AG, part of Springer Nature 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Printed on acid-free paper This Springer imprint is published by the registered company Springer International Publishing AG part of Springer Nature The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Foreword Improving the success of anticancer therapies in recent decades has led to a marked prolongation of survival in patients suffering from cancer even in advanced disease. In this extended survival, many patients face persistent lesions or recurrences at the original or distant sites, and the skeleton as a whole is the third most frequent organ affected by distal metastases after the lungs and liver. Bone involvement frequently and seriously affects the life of the patients since it can cause severe pain and functional impairments; in addition, cancer therapy itself can alter bone composition. There is a need of therapies aimed at least at managing these aspects even when an effect on survival is not expected. It is also a public health matter since the burden of disease associated with bone metastases affects a wide population of cancer patients and consumes a relevant amount of health system resources; there- fore, the selection of alternative therapeutic options should be based on solid knowledge. This manual provides an updated overview on the management of bone metastases, which is also clear and comprehensive, proposing an integrated multidisciplinary approach which is being more and more deemed as the most appropriate in many neoplastic diseases. The book covers several aspects of what is known about bone metastasis including basic science, e.g., bone physiology and mechanisms determining homing and growth of tumor cells. Chapters address the different types of therapies, drugs, surgery, and physical agents, and also rehabilitation and possible complications are not neglected. Considerable attention is paid to the process of therapeutic deci- sion, which is particularly important and complex in this field where most of the cases are not treated with curative intent but rather to limit the symptoms of the evolving disease and to ensure a better quality of the residual life. This book provides a description of evidence available, decisional algorithms, and software to assist in the complex path of clinical decision which has to be taken at an individualized level, considering clinical status and expected sur- vival to balance the impact of therapies and benefits expected. Much attention is dedicated to orthopedic surgery, which has a key role in the management of bone metastases with several possible solutions and materials extensively described in the book. As it would be expected, several authors from well- known centers contributed to write a manual dealing with such a broad range of topics. v vi Foreword In conclusion, the editors make available to oncologists in general and to those specialized in the treatment of cancer bone metastases a valuable tool to assist them in the clinical management of such conditions. Walter Ricciardi President of the Italian National Institute of Health Rome, Italy Preface It has been estimated by AIRTUM (Italian Association of Cancer Registries) that there have been about 369,000 new diagnoses of cancer in Italy in 2017, approximately 192,000 males and 177,000 females. Overall, there are 1000 new diagnoses of cancer every day. These data are in line with those of the American Cancer Society (ACS), which estimates an incidence of 1.7 million new cases of cancer, half of which are prone to develop bone metastases. Despite the increased incidence, an increase in the survival of these patients has been observed in the last few years. According to the ACS, the 5-year overall survival of cancer patients has improved from 49% in the years 1975– 1977 to 69% in the period 2006–2012. This outstanding result is due to the improvement in the integrated approach to the cancer patient. Bone is the most common site for metastasis, mainly because of the con- tribution of breast and prostate cancers, which in postmortem examinations have showed a 70% prevalence of metastatic bone disease. However, bone metastases may occur in a wide variety of bone malignancies, with consider- able morbidity and complex demands on healthcare resources. On the basis of the data of the Medical Expenditure Panel Survey (MEPS), the agency for healthcare research and quality estimated that the direct medical costs for cancer in the USA in 2014 were 87.8 billion dollars. Fifty-eight percent of those costs were for hospital outpatient or office-based visits and 27% were for inpatient hospital stays. In fact, even though most cases of bone metastases are asymptomatic, these can cause pain and are complicated by the so-called skeletal-related events (SRE), which include pathologic fractures and impending fractures, spinal cord compression, and hypercalcemia. Therefore, the occurrence of a skeletal metastasis represents a severe event which negatively affects the prognosis of the cancer patient, above all if the lesion requires surgery. On average, a patient with metastatic disease will experience SREs once every 3 to 6 months, usually clustering around periods of progression of the disease, and becoming more frequent as the disease becomes more extensive. Moreover, occurrence of SREs is associated with an increase in the frequency of invasive procedures and in the number of outpatient and daycare visits of the oncologic patient. This book aims to develop awareness of the need for an integrated approach to patients affected by bone metastases, by presenting major advances in medical, surgical, and radiological interventions for patients with metastatic cancer to the bone. Moreover, the approach to the cancer patient in terms of vii viii Preface characterization of the patient's disease is fully discussed. The book consists of five parts, different in terms of contents and perspective with respect to the management of the bone cancer patient. Part I is entitled “biology of bone metastases” and is devoted to the char- acterization of the pathology of bone metastasis, and to the medical treat- ments available today for patients with bone metastases, including bone modifying agents and anticancer agents with bone effects, and the bone-tar- geted therapies used in the adjuvant setting. Part II is devoted to the “approach to the patients” affected by bone metas- tases, by giving guidelines to the clinician on how to characterize the single patient affected by bone metastases. In particular, some of the most difficult challenges for clinicians, like the determination of the patient's survival and the risk of fractures of bone lesions (the so-called impending fractures), are presented in a complete fashion. These issues influence most of the current work of oncologists, clinicians, and surgeons and represent the main issues in the care of the oncologic patient with metastatic disease to the bone. Current standards of radiation therapy to the long bones, pelvis, and spine are pre- sented here indicating how this kind of treatment is currently crucial to the management of bone cancer patients. Finally, the guidelines of treatment of patients with metastases to the different bone segment (namely spine, long bone, and pelvis) are provided in separate chapters. We are extremely proud of this work, since it reflects the efforts of the Italian Orthopaedic Society (SIOT) Bone Metastases Study Group that in the last few years has drawn simple and reproducible criteria for decision-making in the clinical setting of the bone metastatic patient. Part III deals with the surgical management of patients with bone metasta- ses. In the last few years the development of newer instrumentation systems and biomaterials, together with less aggressive anesthesiological care, is reflected in more targeted surgery, and when possible with more aggressive surgery, even in the metastatic patient. This makes sense thinking of the increased survival time after surgery of the patients with metastases to the bone; therefore the implants and surgical techniques should be targeted to anatomical location, type of tumors, sensitivity to radiation, and adjuvant therapies, and above all to patients’ survival. Many chapters are dedicated to the complications more commonly associated with these surgical interven- tions. In particular, infections, fractures, and failures around tumor implants are among the most feared complications that can occur in these patients. Two outstanding contributions are devoted to the correct staging and preop- erative planning of patients before surgery—“Think, stage, then act” is a simple but quintessential rule!—and to the common pitfalls occurring in the management of patients affected by skeletal metastases, which most often determine the final surgical results. A full chapter is dedicated to the rehabili- tation of patients operated on for metastatic disease to the bone, since after the management of pain and disability, the return to function is our main aim for these patients. Dealing with immunocompromised patients, or when the expected sur- vival is not enough to accept the risks associated with surgical interventions, surgery is sometimes not an option for patients affected by metastases to the Preface ix bone. In this context, clinicians and interventional radiologists have devel- oped newer minimally invasive techniques to manage these patients. This is the main topic of Part IV. In this context, other techniques like electrochemo- therapy have been introduced into clinical practice in controlled studies and are now available to clinicians for the management of selected patients with bone metastases. We end this book with a look to the contemporary directions in the man- agement of bone metastases—what’s new—and to the potential future direc- tions of this discipline. We particularly thank Prof. Capanna for his visionary contribution to this book with his chapter entitled “Future Directions,” which represents a leap into the next generation of treatments for patients affected by bone metastases. We wish to thank our contributors for the outstanding work expressed in their respective chapters. They are well-known leading specialists worldwide in the topic of metastases to the bone and osteoncology, and we trust that this textbook will represent an international reference in the field of bone metas- tases. We do recognize that, given the rate of advancement of the knowledge in this field, some topics will need constant revision and update. However, today this textbook represents a collection of the most current knowledge on this subject and definitely reflects the tremendous advancements in the stan- dard care of these patients worldwide. Rome, Italy Vincenzo Denaro Alberto Di Martino Andrea Piccioli Contents Part I B iology of Bone Metastases 1 Pathology of Bone Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Carlo Della Rocca and Claudio Di Cristofano 2 Bone-Modifying Agents and Anticancer Agents with Bone Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Daniele Santini, Francesco Pantano, Michele Iuliani, Giulia Ribelli, Paolo Manca, Bruno Vincenzi, and Giuseppe Tonini 3 Bone-Targeted Therapies in Adjuvant Setting . . . . . . . . . . . . . . 27 Toni Ibrahim and Federica Recine Part II Approach to the Patient 4 Estimating Survival in Patients with Skeletal Metastases Using PATHFx: An Adaptive, Validated, Clinical Decision Support Tool . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Jonathan A. Forsberg and Rikard Wedin 5 How Expected Survival Influences the Choice of Surgical Procedure in Metastatic Bone Disease . . . . . . . . . . . . . . . . . . . . 49 Panagiotis Tsagozis, Jonathan Forsberg, Henrik C. F. Bauer, and Rikard Wedin 6 The Role of Radiotherapy in Long Bone Metastases and Pelvis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Michele Fiore, Carla Germana Rinaldi, and Sara Ramella 7 The Role of Radiotherapy in Spinal Metastases . . . . . . . . . . . . 65 Francesca De Felice, Daniela Musio, and Vincenzo Tombolini 8 Management of Metastases to the Spine and Sacrum . . . . . . . . 73 Riccardo Ghermandi, Gisberto Evangelisti, Marco Girolami, Valerio Pipola, Stefano Bandiera, Giovanni Barbanti-Bròdano, Cristiana Griffoni, Giuseppe Tedesco, Silvia Terzi, and Alessandro Gasbarrini xi